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Home , T helper cell

The Five Elements of Th1-Th2 System

Shengrong Zou*

Information Engineering College, Yangzhou University , Yangzhou 225009 JiangSu ,PR China

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Abstract The T helper (Th) , Th1/Th2, are acquired upon interaction of a naive and an presenting cell (APC). Naive T helper cells may differentiate into either , and the actual outcome is determined by the density and avidity of the antigenic determinants presented by the APC, and the APCs inherent costimulatory properties. Until recently it was thought that differentiation is further affected by . In our work, We have specified aspects of T-cell networks using B method of software engineering. With this model, we are able to run verification with B-toolkit and allow us to compare the dynamic behavior of the model to actual experimental data from College of Animal Science and Veterinary Medicine. Here we present a Wu-Hsing model of Th1-Th2 system.

Keywords: ; Cytokine network ; Th1-Th2 system; Wu-Hsing

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Contents

1. Introduction……………………………………………….……………………………………………..……………………...1 2. The Wu-Hsing model…….…………………..…………………………………….……………………..……………….…….1 3. The five elements of Th1-Th2 system……..………………………. …………….………….….…………………….….2 3.1 Five elements……………………………………………………………….…………………………………………….3 3.2 Promotion……………………………………………………………………………………………….………………..3 3.3 Inhibition…………………………………………………………………………………………………………………4 4. Conclusion……………………………………………………………………….…………………………..……….…………4 Acknowledgements………………………………………………...……………………………...….….……………………...4 References………………………………………………………………………….….…………………….…4 ______

* Tel: +86 514 87339226 ; fax : +86 514 7887937. E-mail address: [email protected](SR. Zou).

1 Introduction opposite forces of change which complement and cyclically give rise to one another, operated through Although many details of particular cytokine the physical mechanism of "the five material interactions have been elucidated and the effects of agents," or Wu-Hsing . cytokines on a myriad of cellular functions have These five material agents are been described, practically nothing is known about wood-fire-earth-metal-water and are grouped either the behavior of the network as a whole[1]. Perhaps in the order by which they produce one another the most important features of the network are (wood gives rise to fire, fire gives rise to earth, earth nonlinearities in cytokine interactions and the gives rise to metal, metal gives rise to water, water presence of positive and negative feedback . gives rise to earth, etc.) or the order by which they Complex nonlinear systems commonly have are conquered by one another: fire is conquered by unusual and nonintuitive properties that may water, water is conquered by earth, earth is include chaotic behavior. These properties make conquered by wood, wood is conquered by metal, the cytokine network too complex to be and metal is conquered by fire, etc. Each of these understood fully by the conventional experimental orders can be used to explain the progression of approach of testing the effects of cytokines or change in just about everything. The five agents, combinations of cytokines on cells in vitro. however, is a metaphysical explanation of the The finding that T cell immune responses could progression of change that is meant to be applied to be divided into those promoting cell mediated every phenomenon one encounters in this changing (Th1) and humoral responses (Th2) has universe: politics, ethics, music, biology, time, had a profound effect on the understanding of seasons, history, etc. immune response generation. With ever increasing The Chinese divided the year into five seasons: knowledge of the , the model has Spring, Summer, Late Summer, Autumn, and Winter. come under criticism, as not all responses easily fit Each of them they described with the attributes of the classification. All cytokine interactions exhibit one of the Five Elements: Wood, Fire, Earth, Metal, nonlinear behavior. In fact , they act in a complex, and Water. When looking at these Five Elements -- intermingled network where one cytokine can or Five Forces -- all around us in , we can influence the production of, and response to, many also discern that these qualities of energy have a other cytokines[2]. A complementary modeling matching counterpart inside every living being. approach based on modern nonlinear dynamic is These forces are the elemental building blocks of now required. In this review we update the model our inner nature. with current thinking regarding the generation and In human anatomy, the is ruled by wood, maintenance of immune responses[3]. the lungs by fire, the heart by earth, the liver by metal, and the kidneys by water. If one has a 2 The Wu-Hsing model of the liver, it is because the liver is being overcome by a fire agent or ---since fire is overcome The thinkers of the early Zhou dynasty attempted by water, one would treat the liver pathogen with a to fuse many of the strains of Chinese thought to water agent. come up with a syncretic and systematic explanation of the universe, the changes that occur in the universe, and the relation of the human world to the physical and divine worlds. Their thought focused on two inventions, both designed to explain the changing world. The principles of yin and yang, spleen that these cytokines cannot be produced also by other cells. Producer cells other than T-cells expressing CD4 include CD8 (+)T-cells, , natural killer cells, B-cells, , mast cells, k idney lung basophils, and other cells. This is why many immunologists define immune responses by the types of cytokines controlling these responses rather than by the types of cells. Both types of T-helper cells can influence and liver heart regulate each other by the cytokines they secrete [15]. For example, IFN-γ, secreted by Th1 cells, Fig.1. Five elements in Chinese medicine can inhibit the proliferation of Th2 cells. IL10, secreted by Th2 cells, can suppress Th1 functions One could endlessly list how the various by inhibiting cytokine production. The Th2 categories of phenomenon fit into Wu-Hsing model. cytokine IL4 inhibits the differentiation and/or What is important to understand is that the five expansion of Th1 cells. It thus appears that these agents explain everything including the progress of functional subsets of helper cells are mutually change in the universe. antagonistic such that the decision of which subset predominates within an infection may determine 3 The Five Elements of Th1-Th2 system also its outcome[16]. Through the activities of the A great deal of experimental data on the cytokines produced, Th1 and Th2 cells can keep regulation of Th1 and Th2 differentiation have been each other in check and prevent inflammatory obtained. Other authors[4-8] have modeled the reactions in response to getting out of Th1-Th2 system, with a variety of approaches and control. areas of emphasis[9,10]. But many essential The main interactions influencing the generation features of this complex system are still not and maintenance of Th1-Th2 system are understood[11]. Here we present a Wu-Hsing model summarized in Fig.2. of Th1/Th2 differentiation and cross regulation. Th1 and Th2 cells arise from a common precursor. When an immune response is initiated, IL-2 naive helper T cells produce (IL)-2 and proliferate. After entering the cell cycle, progeny become competent to produce effector IL-4 IL-12 cytokines[12,13]. Th1 cells, but not Th2 cells, secrete IL2 , (IFN )-γ, and tumor necrosis factor(TNF)-β , whereas Th2 cells, but not Th1 cells, express IL4 , IL5 , IL6 , and IL10 . The relative balance of Th1 vs. Th2 cytokine IL-10 IFN-γ expression is thought to play a critical role in the regulation of cellular immune responses, with impacts on susceptibility to infectious disease Fig.1. Cytokines are major inducers of Th1 and Th2 subset and/or progression of inflammatory disorders [14]. development. The five elements of Th1-Th2 system are The fact that some of these cytokines have been IL-2,IL-12,IFN- γ ,IL-4 and IL-10. IL-2 promotes designated type-1 or type-2 factors does not imply production of IL-12, IL-12 promotes production of IFN- γ, IFN-γ promotes production of IL-10, IL-10 promotes proliferation, survival and . production of IL-4, IL-4 promotes production of IL-2. IL-10 Produced by mast cells, T cells and inhibits production of IL-2, IL-2 inhibits production of IFN- stromal cells, IL-4 regulates the differentiation of γ , IFN- γ inhibits production of IL-4, IL-4 inhibits naive CD4+ T cells into helper Th2 cells, which production of IL-12 , IL-12 inhibits production of IL-10. favor a humoral immune response. Another dominant function of IL-4 is the regulation of 3.1 Five elements immunoglobulin class switching to the IgG1 and IgE isotypes. Excessive IL-4 production by Th2 IL-2 is a cytokine with a crucial regulatory role in cells has been associated with elevated IgE the immune system. In healthy humans (or production and . mammals), expression of IL-2 is restricted to the IL-10 is an immunosuppressive cytokine effector subset of T-helper —that is, produced by a variety of mammalian cell types activated naive CD4 T-helper cells and including , monocytes, T cells, B cells Th1-committed T-helper clones. IL-2 acts as a T-cell and keratinocytes. IL-10 inhibits the expression of growth factor; it sensitizes activated T cells to proinflammatory cytokines such as IL-1 and TNF-α. activation-induced cell death (AICD); it promotes Like IL-4, IL-10 enhances humoral immune the maturation of cytotoxic T lymphocytes and responses and attenuates cell-mediated immune -activated killer activity; and it reactions. enhances germicidal and cytotoxic function of natural killer (NK) cells, B-cells, monocytes, and macrophages. 3.2 Promotion IL-12 is a regulatory produced by activated B lymphocytes and macrophages. The IL-2---IL-12 IL-2 promotes the proliferation, biological activities of IL-12 include the stimulation differentiation, and survival of target cells. of growth of activated CD4 and CD8+T cells and Subsequent to their expansion, the differentiated NK cells. Human IL-12 also promotes the function of both T helper cells and T cytolytic cells development of proinflammatory/Th1-like CD4+ is dependent upon an adequate supply of IL-2. cells and cytotoxic CD8 T cells. [17,18]. IFN-γ is an acid-labile interferon produced by IL-12---IFN- γ IL-12 is especially important CD4 and CD8 T lymphocytes as well as activated because its expression during infection regulates NK cells. IFN-γ receptors are present in most innate responses and determines the type and immune cells, which respond to IFN-γ signaling duration of adaptive immune response. IL-12 by increasing the surface expression of class I induces IFN-γ production by NK, T cells, dendritic major histocompatibility complex(MHC) . This cells (DC), and macrophages. IL-12 promotes the promotes the presentation of antigen to T-helper differentiation of naive CD4+ T cells into Th1 cells (CD4+) cells. IFN- γ signaling in APC and that produce IFN- γ and aid in cell-mediated antigen-recognizing B and T lymphocytes regulate immunity[19]. the antigen-specific phases of the immune response. IFN-γ---IL10 Recombinant murine IFN-γwas Additionally, IFN- γ stimulates a number of found to possess maturation factor activity lymphoid cell functions including the anti-microbial for resting splenic B cells and the comparable B cell and anti-tumor responses of macrophages, NK cells, tumor line WEHI-279.1. IFN-γ may be one of and . several molecules with a direct role in driving the IL-4 is a pleiotropic cytokine that regulates maturation of resting B cells to active diverse T and B cell responses including cell immunoglobulin secretion[20]. IL-10---IL-4 IL-10 inhibits production of IL-2 4 Conclusion and TNF- , but not IL-4 when T cells were stimulated without APCs [21]. IL-10 acts as a The crucial cell for immune system control is the costimulator of the proliferation of mast cells (in the T-cell. In Th1-Th2 system, two types of T-helper presence of IL-3 and/or IL-4 ) and peripheral cells have been defined on the basis of their lymphocytes. cytokine secretion patterns[29]. The decision of a IL-4---IL-2 IL-2 and IL-4 are important growth to differentiate into Th1 or Th2 is and differentiation factors for B and T cells. IL-4 crucial, since to a first approximation it determines antagonizes the effect of IL-2 on B cells and some T whether a cell-mediated or humoral immune cells while it synergizes with IL-2 on other T response is triggered against a particular pathogen, cells[22]. which profoundly influences disease outcome[30]. In our work, We have specified aspects of T-cell 3.3 Inhibition cytokine networks using B method of software engineering. With this model, we are able to run IL-10---L-2 IL10 , secreted by Th2 cells, can verification with B-toolkit and allow us to compare suppress Th1 functions by inhibiting cytokine the dynamic behavior of the model to actual production. IL10 inhibits the synthesis of a number experimental data from College of Animal Science of cytokines such as IFN-γ, IL2 and TNF-β in Th1 and Veterinary Medicine. This study shows that T-helper subpopulations of T-cells[23]. IL-2, IL-12, IFN- γ , IL-10, IL-4 are crucial IL-2---IFN-γ IL-2 can promote expression of regulator of Th1-Th2 system. This model therefore CTLA-4, a negative regulator of TCR signals, may have crucial significance in the development of which competes with the positive, costimulatory therapeutic strategies for bio-pharmacologic molecule, CD28. In addition to positive influences intervention in cytokine-mediated inflammatory attributable to IL-2, there are negative feedback process and infections. regulatory effects of IL-2 that function to limit the ultimate immune response and inhibit production of Acknowledgements IFN-γ[24]. 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